Prosthetic Tissue Valves

ABSTRACT

A prosthetic valve comprising a conical shaped sheet member comprising an extracellular matrix (ECM) composition, the sheet member having a plurality of open slit regions that are disposed uniformly on linear planes that are parallel to the sheet member longitudinal axis, and a proximal annulus engagement end diameter and length ratio in the range of 5:1 to 2:1.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of U.S.application Ser. No. 14/960,354, filed on Dec. 5, 2015, which is acontinuation-in-part application of U.S. application Ser. No.14/229,854, filed on Mar. 29, 2014, now U.S. Pat. No. 9,308,084, whichclaims priority to U.S. Provisional Application No. 61/819,232, filed onMay 3, 2013.

FIELD OF THE INVENTION

The present invention generally relates to prosthetic valves forreplacing defective cardiovascular valves. More particularly, thepresent invention relates to prosthetic atrioventricular valves andmethods for anchoring same to cardiovascular structures and/or tissue.

BACKGROUND OF THE INVENTION

As is well known in the art, the human heart has four valves thatcontrol blood flow circulating through the human body. Referring toFIGS. 1A and 1B, on the left side of the heart 100 is the mitral valve102, located between the left atrium 104 and the left ventricle 106, andthe aortic valve 108, located between the left ventricle 106 and theaorta 110. Both of these valves direct oxygenated blood from the lungsinto the aorta 110 for distribution through the body.

The tricuspid valve 112, located between the right atrium 114 and theright ventricle 116, and the pulmonary valve 118, located between theright ventricle 116 and the pulmonary artery 120, however, are situatedon the right side of the heart 100 and direct deoxygenated blood fromthe body to the lungs.

Referring now to FIGS. 1C and 1D, there are also generally fivepapillary muscles in the heart 100; three in the right ventricle 116 andtwo in the left ventricle 106. The anterior, posterior and septalpapillary muscles 117 a, 117 b, 117 c of the right ventricle 116 eachattach via chordae tendinae 113 a, 113 b, 113 c to the tricuspid valve112. The anterior and posterior papillary muscles 119 a, 119 b of theleft ventricle 106 attach via chordae tendinae 103 a, 103 b to themitral valve 102 (see also FIG. 1E).

Since heart valves are passive structures that simply open and close inresponse to differential pressures, the issues that can develop withvalves are typically classified into two categories: (i) stenosis, inwhich a valve does not open properly, and (ii) insufficiency (alsocalled regurgitation), in which a valve does not close properly.

Stenosis and insufficiency can occur as a result of severalabnormalities, including damage or severance of one or more chordeae orseveral disease states. Stenosis and insufficiency can also occurconcomitantly in the same valve or in different valves.

Both of the noted valve abnormalities can adversely affect organfunction and result in heart failure. By way of example, referring firstto FIG. 1E, there is shown normal blood flow (denoted “BF_(N)”)proximate the mitral valve 102 during closure. Referring now to FIG. 1F,there is shown abnormal blood flow (denoted “BF_(A)”) or regurgitationcaused by a prolapsed mitral valve 102 p. As illustrated in FIG. 1F, theregurgitated blood “BF_(A)” flows back into the left atrium, which can,if severe, result in heart failure.

In addition to stenosis and insufficiency of a heart valve, surgicalintervention may also be required for certain types of bacterial orfungal infections, wherein the valve may continue to function normally,but nevertheless harbors an overgrowth of bacteria (i.e. “vegetation”)on the valve leaflets. The vegetation can, and in many instances will,flake off (i.e. “embolize”) and lodge downstream in a vital artery.

If such vegetation is present on the valves of the left side (i.e., thesystemic circulation side) of the heart, embolization can, and oftenwill, result in sudden loss of the blood supply to the affected bodyorgan and immediate malfunction of that organ. The organ most commonlyaffected by such embolization is the brain, in which case the patientcan, and in many instances will, suffer a stroke.

Likewise, bacterial or fungal vegetation on the tricuspid valve canembolize to the lungs. The noted embolization can, and in many instanceswill, result in lung dysfunction.

Treatment of the noted heart valve dysfunctions typically comprisesreparation of the diseased heart valve with preservation of thepatient's own valve or replacement of the valve with a mechanical orbioprosthetic valve, i.e. a prosthetic valve.

Various prosthetic heart valves have thus been developed for replacementof natural diseased or defective heart valves. Illustrative are thetubular prosthetic tissue valves disclosed in Applicant's U.S. Pat. Nos.9,044,319, 8,709,076 and 8,790,397, and Co-Pending U.S. application Ser.Nos. 13/560,573, 13/804,683, 13/480,347 and 13/480,324. A furthertubular prosthetic valve is disclosed in U.S. Pat. Nos. 8,257,434 and7,998,196.

Heart valve replacement requires a great deal of skill and concentrationto achieve a secure and reliable attachment of a prosthetic valve to acardiovascular structure or tissue. Various surgical methods forimplanting a prosthetic valve have thus been developed.

The most common surgical method that is employed to implant a prostheticvalve (mitral or tricuspid) comprises suturing a circular synthetic ringof a prosthetic valve to the annular tissue of the heart where adiseased valve has been removed.

A major problem associated with prosthetic valves is tissue valves withgluteraldehyde cross-linked leaflets will calcify and deteriorate overtime.

Another problem is mechanical valves will require anticoagulationagents, such as Coumadin, which can cause side effects in high doses,such as uncontrolled bleeding.

Another problem is the valves do not remodel into normal tissue capableof regeneration and self repair.

Another problem is many valves must be placed with open heart surgerywhile the patient is on a heart-lung machine.

There is thus a need to provide improved prosthetic tissue valves andmethods for attaching same to cardiovascular structures and/or tissuethat maintain or enhance the structural integrity of the valve whensubjected to cardiac cycle induced stress.

It is therefore an object of the present invention to provide improvedprosthetic tissue valves and methods for implanting same that overcomethe drawbacks and disadvantages associated with conventional prostheticatrioventricular valves.

It is another object of the present invention to provide improvedprosthetic tissue valves and methods for attaching same tocardiovascular structures and/or tissue that maintain or enhance thestructural integrity of the valve when subjected to cardiac cycleinduced stress.

It is another object of the present invention to provide improvedprosthetic tissue valves and methods for attaching same tocardiovascular structures and/or tissue that preserve the structuralintegrity of the cardiovascular structure(s) when attached thereto.

It is another object of the present invention to provide improvedmethods for securely attaching prosthetic tissue valves tocardiovascular structures and/or tissue.

It is another object of the present invention to provide prosthetictissue valves having means for secure, reliable, and consistently highlyeffective attachment to cardiovascular structures and/or tissue.

It is another object of the present invention to provide extracellularmatrix (ECM) prosthetic tissue valves that induce host tissueproliferation, bioremodeling and regeneration of new tissue and tissuestructures with site-specific structural and functional properties.

It is another object of the present invention to provide ECM prosthetictissue valves that induce adaptive regeneration.

It is another object of the present invention to provide ECM prosthetictissue valves that are capable of administering a pharmacological agentto host tissue and, thereby produce a desired biological and/ortherapeutic effect.

SUMMARY OF THE INVENTION

The present invention is directed to prosthetic tissue valves that canbe readily employed to selectively replace diseased or defective heartvalves, and methods for attaching (or anchoring) same to cardiovascularstructures and/or tissue.

In some embodiments of the invention, the prosthetic tissue valvescomprise continuous tubular members.

In some embodiments of the invention, the prosthetic tissue valvescomprise continuous conical shaped structural members.

In some embodiments of the invention, the proximal end of the prosthetictissue valves comprise an annular ring that is designed and configuredto securely engage the prosthetic tissue valves to a valve annulus and,hence, cardiovascular tissue associated therewith.

In some embodiments of the invention, the distal end of the prosthetictissue valves having conical shaped structural members also comprise astructural ring.

According to the invention, the tubular member, conical shapedstructural member, annular ring and structural ring can comprise variousbiocompatible materials.

In some embodiments of the invention, the tubular member and/or conicalshaped structural member and/or annular ring and/or structural ringcomprise an ECM composition comprising acellular ECM derived from amammalian tissue source.

In a preferred embodiment of the invention, the mammalian tissue sourceis selected from the group comprising small intestine submucosa (SIS),urinary bladder submucosa (UBS), stomach submucosa (SS), central nervoussystem tissue, mesodermal tissue, i.e. mesothelial tissue, dermalextracellular matrix, subcutaneous extracellular matrix,gastrointestinal extracellular matrix, i.e. large and small intestines,tissue surrounding growing bone, placental extracellular matrix, omentumextracellular matrix, cardiac extracellular matrix, e.g., pericardiumand/or myocardium, kidney extracellular matrix, pancreas extracellularmatrix, lung extracellular matrix, and combinations thereof.

In some embodiments of the invention, the ECM composition (and, hence,tubular member and/or conical shaped structural member and/or annularring and/or structural ring formed therefrom) further comprises at leastone additional biologically active agent or composition, i.e. an agentthat induces or modulates a physiological or biological process, orcellular activity, e.g., induces proliferation, and/or growth and/orregeneration of tissue.

In some embodiments of the invention, the biologically active agentcomprises a growth factor, including, without limitation, transforminggrowth factor alpha (TGF-α), transforming growth factor beta (TGF-β),fibroblast growth factor-2 (FGF-2), and vascular epithelial growthfactor (VEGF).

In some embodiments of the invention, the ECM composition (and, hence,tubular member and/or conical shaped structural member and/or annularring and/or structural ring formed therefrom) further comprises at leastone pharmacological agent or composition (or drug), i.e. an agent orcomposition that is capable of producing a desired biological effect invivo, e.g., stimulation or suppression of apoptosis, stimulation orsuppression of an immune response, etc.

In some embodiments of the invention, the pharmacological agentcomprises an anti-inflammatory agent.

In some embodiments of the invention, the pharmacological agentcomprises a statin, i.e. a HMG-CoA reductase inhibitor.

In some embodiments of the invention, the annular ring and/or structuralring comprise a biocompatible polymeric material.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages will become apparent from the followingand more particular description of the preferred embodiments of theinvention, as illustrated in the accompanying drawings, and in whichlike referenced characters generally refer to the same parts or elementsthroughout the views, and in which:

FIGS. 1A-1D are schematic illustrations of a human heart;

FIG. 1E is an illustration of a normal mitral valve;

FIG. 1F is an illustration of a prolapsed mitral valve;

FIG. 2 is a perspective view of one embodiment of a prosthetic tissuevalve, in accordance with the invention;

FIG. 3 is a side plane view of the prosthetic tissue valve shown in FIG.2, in accordance with the invention;

FIG. 4 is a perspective partial sectional view of another embodiment ofa prosthetic tissue valve shown in FIG. 2 having an annular ringdisposed at the proximal end of the valve, in accordance with theinvention;

FIG. 5 is a side plane view of the prosthetic tissue valve shown in FIG.4, in accordance with the invention;

FIG. 6 is an illustration of the prosthetic tissue valve shown in FIG. 4secured to the mitral valve annulus region and papillary muscles, inaccordance with the invention;

FIG. 7A is a perspective view of another embodiment of a prosthetictissue valve, in accordance with the invention;

FIG. 7B is an end plane view of the prosthetic tissue valve shown inFIG. 7A, in accordance with the invention;

FIG. 7C is a perspective view partial sectional of another embodiment ofa prosthetic tissue valve shown in FIG. 7A having an annular ringdisposed at the proximal end of the valve, in accordance with theinvention;

FIG. 7D is a perspective view partial sectional of yet anotherembodiment of a prosthetic tissue valve shown in FIG. 7A having anannular ring disposed at the proximal end of the valve and a structuralring disposed at the distal end of the valve, in accordance with theinvention;

FIG. 8A is a side plan view of another embodiment of a prosthetic tissuevalve in a pre-formed configuration, in accordance with the invention;

FIG. 8B is a perspective view of the prosthetic tissue valve shown inFIG. 8A in a formed configuration, in accordance with the invention;

FIG. 8C is a perspective partial sectional view of another embodiment ofa prosthetic tissue valve shown in FIG. 8B having an annular ringdisposed at the proximal end of the valve, in accordance with theinvention;

FIG. 8D is a perspective partial sectional view of yet anotherembodiment of a prosthetic tissue valve shown in FIG. 8B having anannular ring disposed at the proximal end of the valve and a structuralring disposed at the distal end of the valve, in accordance with theinvention;

FIG. 9 is an illustration of the prosthetic tissue valve shown in FIG.7C secured to the mitral valve annulus region, in accordance with theinvention;

FIG. 10 is an illustration of the prosthetic tissue valve shown in FIG.8C secured to the mitral valve annulus region, in accordance with theinvention; and

FIG. 11 is an illustration of the prosthetic tissue valve shown in FIG.8B secured to the mitral valve annulus region, in accordance with theinvention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particularlyexemplified apparatus, systems, structures or methods as such may, ofcourse, vary. Thus, although a number of apparatus, systems and methodssimilar or equivalent to those described herein can be used in thepractice of the present invention, the preferred apparatus, systems,structures and methods are described herein.

It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments of the invention only andis not intended to be limiting.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one having ordinaryskill in the art to which the invention pertains.

Further, all publications, patents and patent applications cited herein,whether supra or infra, are hereby incorporated by reference in theirentirety.

As used in this specification and the appended claims, the singularforms “a, “an” and “the” include plural referents unless the contentclearly dictates otherwise. Thus, for example, reference to “apharmacological agent” includes two or more such agents and the like.

Further, ranges can be expressed herein as from “about” or“approximately” one particular value, and/or to “about” or“approximately” another particular value. When such a range isexpressed, another embodiment includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about” or“approximately”, it will be understood that the particular value formsanother embodiment. It will be further understood that the endpoints ofeach of the ranges are significant both in relation to the otherendpoint, and independently of the other endpoint.

It is also understood that there are a number of values disclosedherein, and that each value is also herein disclosed as “about” or“approximately” that particular value in addition to the value itself.For example, if the value “10” is disclosed, then “approximately 10” isalso disclosed. It is also understood that when a value is disclosedthat “less than or equal to” the value, “greater than or equal to thevalue” and possible ranges between values are also disclosed, asappropriately understood by the skilled artisan. For example, if thevalue “10” is disclosed then “less than or equal to 10” as well as“greater than or equal to 10” is also disclosed.

Definitions

The terms “extracellular matrix”, “ECM”, and “ECM material” are usedinterchangeably herein, and mean and include a collagen-rich substancethat is found in between cells in mammalian tissue, and any materialprocessed therefrom, e.g. decellularized ECM. According to theinvention, ECM can be derived from a variety of mammalian tissuesources, including, without limitation, small intestine submucosa (SIS),urinary bladder submucosa (UBS), stomach submucosa (SS), central nervoussystem tissue, epithelium of mesodermal origin, i.e. mesothelial tissue,dermal extracellular matrix, subcutaneous extracellular matrix,gastrointestinal extracellular matrix, i.e. large and small intestines,tissue surrounding growing bone, placental extracellular matrix, omentumextracellular matrix, cardiac extracellular matrix, e.g., pericardiumand/or myocardium, kidney extracellular matrix, pancreas extracellularmatrix, lung extracellular matrix, and combinations thereof. The ECMmaterial can also comprise collagen from mammalian sources.

The term “acellular ECM”, as used herein, means and includes ECM thathas a reduced content of cells, i.e. decellularized ECM.

The terms “urinary bladder submucosa (UBS)”, “small intestine submucosa(SIS)” and “stomach submucosa (SS)” also mean and include any UBS and/orSIS and/or SS material that includes the tunica mucosa (which includesthe transitional epithelial layer and the tunica propria), submucosallayer, one or more layers of muscularis, and adventitia (a looseconnective tissue layer) associated therewith.

ECM can also be derived from basement membrane of mammaliantissue/organs, including, without limitation, urinary basement membrane(UBM), liver basement membrane (LBM), and amnion, chorion, allograftpericardium, allograft acellular dermis, amniotic membrane, Wharton'sjelly, and combinations thereof.

Additional sources of mammalian basement membrane include, withoutlimitation, spleen, lymph nodes, salivary glands, prostate, pancreas andother secreting glands.

According to the invention, the ECM can be derived from xenogeneic andallogeneic tissue sources.

ECM can also be derived from other sources, including, withoutlimitation, collagen from plant sources and synthesized extracellularmatrices, i.e. cell cultures.

The term “angiogenesis”, as used herein, means a physiologic processinvolving the growth of new blood vessels from pre-existing bloodvessels.

The term “neovascularization”, as used herein, means and includes theformation of functional vascular networks that can be perfused by bloodor blood components. Neovascularization includes angiogenesis, buddingangiogenesis, intussuceptive angiogenesis, sprouting angiogenesis,therapeutic angiogenesis and vasculogenesis.

The term “biologically active agent”, as used herein, means and includesagent that induces or modulates a physiological or biological process,or cellular activity, e.g., induces proliferation, and/or growth and/orregeneration of tissue.

The term “biologically active agent” thus means and includes, withoutlimitation, the following growth factors: platelet derived growth factor(PDGF), epidermal growth factor (EGF), transforming growth factor alpha(TGF-α), transforming growth factor beta (TGF-β), fibroblast growthfactor-2 (FGF-2), vascular epithelial growth factor (VEGF), hepatocytegrowth factor (HGF), insulin-like growth factor (IGF), nerve growthfactor (NGF), platlet derived growth factor (PDGF), tumor necrosisfactor alpha (TNA-alpha), and placental growth factor (PLGF).

The term “biologically active agent” also means and includes, withoutlimitation, human embryonic stem cells, fetal cardiomyocytes,myofibroblasts, mesenchymal stem cells, autotransplated expandedcardiomyocytes, adipocytes, totipotent cells, pluripotent cells, bloodstem cells, myoblasts, adult stem cells, bone marrow cells, mesenchymalcells, embryonic stem cells, parenchymal cells, epithelial cells,endothelial cells, mesothelial cells, fibroblasts, osteoblasts,chondrocytes, exogenous cells, endogenous cells, stem cells,hematopoietic stem cells, bone-marrow derived progenitor cells,myocardial cells, skeletal cells, fetal cells, undifferentiated cells,multi-potent progenitor cells, unipotent progenitor cells, monocytes,cardiac myoblasts, skeletal myoblasts, macrophages, capillaryendothelial cells, xenogeneic cells, allogeneic cells, and post-natalstem cells.

The term “biologically active agent” also means and includes, withoutlimitation, the following biologically active agents (referred tointerchangeably herein as a “protein”, “peptide” and “polypeptide”):collagen (types I-V), proteoglycans, glycosaminoglycans (GAGs),glycoproteins, growth factors, cytokines, cell-surface associatedproteins, cell adhesion molecules (CAM), angiogenic growth factors,endothelial ligands, matrikines, cadherins, immuoglobins, fibrilcollagens, non-fibrallar collagens, basement membrane collagens,multiplexins, small-leucine rich proteoglycans, decorins, biglycans,fibromodulins, keratocans, lumicans, epiphycans, heparin sulfateproteoglycans, perlecans, agrins, testicans, syndecans, glypicans,serglycins, selectins, lecticans, aggrecans, versicans, neurocans,brevicans, cytoplasmic domain-44 (CD-44), macrophage stimulatingfactors, amyloid precursor proteins, heparins, chondroitin sulfate B(dermatan sulfate), chondroitin sulfate A, heparin sulfates, hyaluronicacids, fibronectins, tenascins, elastins, fibrillins, laminins,nidogen/enactins, fibulin I, fibulin II, integrins, transmembranemolecules, thrombospondins, osteopontins, and angiotensin convertingenzymes (ACE).

The term “biologically active composition”, as used herein, means andincludes a composition comprising a “biologically active agent”.

The terms “pharmacological agent”, “active agent” and “drug” are usedinterchangeably herein, and mean and include an agent, drug, compound,composition of matter or mixture thereof, including its formulation,which provides some therapeutic, often beneficial, effect. This includesany physiologically or pharmacologically active substance that producesa localized or systemic effect or effects in animals, including warmblooded mammals, humans and primates; avians; domestic household or farmanimals, such as cats, dogs, sheep, goats, cattle, horses and pigs;laboratory animals, such as mice, rats and guinea pigs; fish; reptiles;zoo and wild animals; and the like.

The terms “pharmacological agent”, “active agent” and “drug” thus meanand include, without limitation, antibiotics, anti-arrhythmic agents,anti-viral agents, analgesics, steroidal anti-inflammatories,non-steroidal anti-inflammatories, anti-neoplastics, anti-spasmodics,modulators of cell-extracellular matrix interactions, proteins,hormones, growth factors, matrix metalloproteinases (MMPs), enzymes andenzyme inhibitors, anticoagulants and/or antithrombotic agents, DNA,RNA, modified DNA and RNA, NSAIDs, inhibitors of DNA, RNA or proteinsynthesis, polypeptides, oligonucleotides, polynucleotides,nucleoproteins, compounds modulating cell migration, compoundsmodulating proliferation and growth of tissue, and vasodilating agents.

The terms “pharmacological agent”, “active agent” and “drug” also meanand include, without limitation, atropine, tropicamide, dexamethasone,dexamethasone phosphate, betamethasone, betamethasone phosphate,prednisolone, triamcinolone, triamcinolone acetonide, fluocinoloneacetonide, anecortave acetate, budesonide, cyclosporine, FK-506,rapamycin, ruboxistaurin, midostaurin, flurbiprofen, suprofen,ketoprofen, diclofenac, ketorolac, nepafenac, lidocaine, neomycin,polymyxin b, bacitracin, gramicidin, gentamicin, oyxtetracycline,ciprofloxacin, ofloxacin, tobramycin, amikacin, vancomycin, cefazolin,ticarcillin, chloramphenicol, miconazole, itraconazole, trifluridine,vidarabine, ganciclovir, acyclovir, cidofovir, ara-amp, foscarnet,idoxuridine, adefovir dipivoxil, methotrexate, carboplatin,phenylephrine, epinephrine, dipivefrin, timolol, 6-hydroxydopamine,betaxolol, pilocarpine, carbachol, physostigmine, demecarium,dorzolamide, brinzolamide, latanoprost, sodium hyaluronate, insulin,verteporfin, pegaptanib, ranibizumab, and other antibodies,antineoplastics, anti-VEGFs, ciliary neurotrophic factor, brain-derivedneurotrophic factor, bFGF, Caspase-1 inhibitors, Caspase-3 inhibitors,α-Adrenoceptors agonists, NMDA antagonists, Glial cell line-derivedneurotrophic factors (GDNF), pigment epithelium-derived factor (PEDF),and NT-3, NT-4, NGF, IGF-2.

The terms “pharmacological agent”, “active agent” and “drug” also meanand include the following Class I-Class V antiarrhythmic agents: (ClassIa) quinidine, procainamide and disopyramide; (Class Ib) lidocaine,phenytoin and mexiletine; (Class Ic) flecainide, propafenone andmoricizine; (Class II) propranolol, esmolol, timolol, metoprolol andatenolol; (Class III) amiodarone, sotalol, ibutilide and dofetilide;(Class IV) verapamil and diltiazem) and (Class V) adenosine and digoxin.

The terms “pharmacological agent”, “active agent” and “drug” also meanand include, without limitation, the following antiobiotics:aminoglycosides, cephalosporins, chloramphenicol, clindamycin,erythromycins, fluoroquinolones, macrolides, azolides, metronidazole,penicillins, tetracyclines, trimethoprim-sulfamethoxazole andvancomycin.

The terms “pharmacological agent”, “active agent” and “drug” also meanand include, without limitation, the following steroids: andranes (e.g.,testosterone), cholestanes, cholic acids, corticosteroids (e.g.,dexamethasone), estraenes (e.g., estradiol) and pregnanes (e.g.,progesterone).

The terms “pharmacological agent”, “active agent” and “drug” also meanand include one or more classes of narcotic analgesics, including,without limitation, morphine, codeine, heroin, hydromorphone,levorphanol, meperidine, methadone, oxycodone, propoxyphene, fentanyl,methadone, naloxone, buprenorphine, butorphanol, nalbuphine andpentazocine.

The terms “pharmacological agent”, “active agent” and “drug” also meanand include one or more classes of topical or local anesthetics,including, without limitation, esters, such as benzocaine,chloroprocaine, cocaine, cyclomethycaine, dimethocaine/larocaine,piperocaine, propoxycaine, procaine/novacaine, proparacaine, andtetracaine/amethocaine. Local anesthetics can also include, withoutlimitation, amides, such as articaine, bupivacaine,cinchocaine/dibucaine, etidocaine, levobupivacaine,lidocaine/lignocaine, mepivacaine, prilocaine, ropivacaine, andtrimecaine. Local anesthetics can further include combinations of theabove from either amides or esters.

As indicated above, the terms “pharmacological agent”, “active agent”and “drug” also mean and include an anti-inflammatory.

The terms “anti-inflammatory” and “anti-inflammatory agent” are alsoused interchangeably herein, and mean and include a “pharmacologicalagent” and/or “active agent formulation”, which, when a therapeuticallyeffective amount is administered to a subject, prevents or treats bodilytissue inflammation i.e. the protective tissue response to injury ordestruction of tissues, which serves to destroy, dilute, or wall offboth the injurious agent and the injured tissues.

Anti-inflammatory agents thus include, without limitation, alclofenac,alclometasone dipropionate, algestone acetonide, alpha amylase,amcinafal, amcinafide, amfenac sodium, amiprilose hydrochloride,anakinra, anirolac, anitrazafen, apazone, balsalazide disodium,bendazac, benoxaprofen, benzydamine hydrochloride, bromelains,broperamole, budesonide, carprofen, cicloprofen, cintazone, cliprofen,clobetasol propionate, clobetasone butyrate, clopirac, cloticasonepropionate, cormethasone acetate, cortodoxone, decanoate, deflazacort,delatestryl, depo-testosterone, desonide, desoximetasone, dexamethasonedipropionate, diclofenac potassium, diclofenac sodium, diflorasonediacetate, diflumidone sodium, diflunisal, difluprednate, diftalone,dimethyl sulfoxide, drocinonide, endrysone, enlimomab, enolicam sodium,epirizole, etodolac, etofenamate, felbinac, fenamole, fenbufen,fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac, flazalone,fluazacort, flufenamic acid, flumizole, flunisolide acetate, flunixin,flunixin meglumine, fluocortin butyl, fluorometholone acetate,fluquazone, flurbiprofen, fluretofen, fluticasone propionate,furaprofen, furobufen, halcinonide, halobetasol propionate, halopredoneacetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol,ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole,intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen,lofemizole hydrochloride, lomoxicam, loteprednol etabonate,meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate,mefenamic acid, mesalamine, meseclazone, mesterolone,methandrostenolone, methenolone, methenolone acetate, methylprednisolonesuleptanate, momiflumate, nabumetone, nandrolone, naproxen, naproxensodium, naproxol, nimazone, olsalazine sodium, orgotein, orpanoxin,oxandrolane, oxaprozin, oxyphenbutazone, oxymetholone, paranylinehydrochloride, pentosan polysulfate sodium, phenbutazone sodiumglycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicamolamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone,proxazole, proxazole citrate, rimexolone, romazarit, salcolex,salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin,stanozolol, sudoxicam, sulindac, suprofen, talmetacin, talniflumate,talosalate, tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam,tesimide, testosterone, testosterone blends, tetrydamine, tiopinac,tixocortol pivalate, tolmetin, tolmetin sodium, triclonide,triflumidate, zidometacin, and zomepirac sodium.

The terms “pharmacological agent”, “active agent” and “drug” also meanand include a statin, i.e. a HMG-CoA reductase inhibitor, including,without limitation, atorvastatin (Lipitor®), cerivastatin, fluvastatin(Lescol®), lovastatin (Mevacor®, Altocor®, Altoprev®), mevastatin,pitavastatin (Livalo ®, Pitava®), pravastatin (Pravachol®, Selektine®,Lipostat®), rosuvastatin (Crestor®), and simvastatin (Zocor®, Lipex®).

The term “pharmacological composition”, as used herein, means andincludes a composition comprising a “pharmacological agent” and/or anyadditional agent or component identified herein.

The term “therapeutically effective”, as used herein, means that theamount of the “pharmacological agent” and/or “biologically active agent”and/or “pharmacological composition” and/or “biologically activecomposition” administered is of sufficient quantity to ameliorate one ormore causes, symptoms, or sequelae of a disease or disorder. Suchamelioration only requires a reduction or alteration, not necessarilyelimination, of the cause, symptom, or sequelae of a disease ordisorder.

The terms “patient” and “subject” are used interchangeably herein, andmean and include warm blooded mammals, humans and primates; avians;domestic household or farm animals, such as cats, dogs, sheep, goats,cattle, horses and pigs; laboratory animals, such as mice, rats andguinea pigs; fish; reptiles; zoo and wild animals; and the like.

The term “comprise” and variations of the term, such as “comprising” and“comprises,” means “including, but not limited to” and is not intendedto exclude, for example, other additives, components, integers or steps.

The following disclosure is provided to further explain in an enablingfashion the best modes of performing one or more embodiments of thepresent invention. The disclosure is further offered to enhance anunderstanding and appreciation for the inventive principles andadvantages thereof, rather than to limit in any manner the invention.The invention is defined solely by the appended claims including anyamendments made during the pendency of this application and allequivalents of those claims as issued.

As stated above, the present invention is directed to prosthetic tissuevalves that can be readily employed to selectively replace diseased ordefective valves in the heart, and methods for attaching (or anchoring)same to cardiovascular structures and/or tissue.

As discussed in detail below, in some embodiments of the invention, theprosthetic tissue valves comprise continuous tubular members.

As indicated above, in some embodiments of the invention, the proximalends of prosthetic tissue valves of the invention comprise an annularring that is designed and configured to securely engage the prosthetictissue valves to a valve annulus (and, hence, cardiovascular tissueassociated therewith).

In some embodiments of the invention, the annular ring comprises atleast one anchoring mechanism that is configured to position theprosthetic tissue valves proximate a valve annulus, and maintain contacttherewith for a pre-determined anchor support time period. According tothe invention, the anchoring mechanisms can comprise various forms andmaterials, such as disclosed in U.S. Pat. No. 9,044,319, which isincorporated by reference herein in its entirety.

In some embodiments of the invention, the anchoring mechanisms areconfigured to position ECM prosthetic tissue valves of the inventionproximate a valve annulus, and maintain contact therewith for apredetermined temporary anchor support period of time within the processof tissue regeneration.

In some embodiments of the invention, the prosthetic valves comprisecontinuous conical shaped structural members.

In some embodiments, the conical shaped structural members and, hence,prosthetic tissue valves formed therefrom, similarly comprise an annularring that is designed and configured to securely engage the conicalshaped structural members and, hence, prosthetic tissue valves formedtherefrom to a valve annulus and, hence, cardiovascular tissueassociated therewith.

In some embodiments of the invention, the distal end of the conicalshaped structural members and, hence, prosthetic tissue valves formedtherefrom, comprises a structural ring.

According to the invention, the tubular members and conical shapedmembers can comprise various biocompatible materials and compositionsformed therefrom.

In some embodiments of the invention, the tubular shaped member andconical shaped member comprise sheet members.

According to the invention, the tubular shaped sheet members and conicalshaped sheet members can comprise single or multi-sheet members.

According to the invention, the sheet(s) can be formed into the tubularand conical shaped members of the invention and secured about the matingedges by various conventional means, e.g., suturing the mating edgestogether.

In some embodiments of the invention, the tubular shaped member and/orannular ring comprise an ECM composition comprising acellular ECMderived from a mammalian tissue source.

In some embodiments of the invention, the conical shaped structuralmember and/or annular ring and/or structural ring similarly comprise anECM composition comprising acellular ECM derived from a mammalian tissuesource.

As discussed in detail herein, it is contemplated that, followingplacement of a prosthetic tissue valve comprising an ECM composition,e.g., a conical shaped structural member comprising an ECM composition,(hereinafter “an ECM prosthetic tissue valve”) on a cardiovascularstructure (or structures) in a subject, e.g. valve annulus, and, hence,cardiovascular tissue associated therewith, the ECM prosthetic tissuevalve will induce “modulated healing” of the cardiovascular structure(s)and tissue associated therewith.

As discussed in detail herein, it is contemplated that, followingplacement of an ECM prosthetic tissue valve on a cardiovascularstructure (or structures) in a subject, the ECM prosthetic tissue valvewill become populated with cells from the subject that will graduallyremodel the ECM into cardiovascular tissue and tissue (and, hence,valve) structures.

It is further contemplated that, following placement of an ECMprosthetic tissue valve on a cardiovascular structure (or structures) ina subject, stem cells will migrate to the ECM prosthetic tissue valvefrom the point(s) at which the valve is attached to the cardiovascularstructure, e.g., valve annulus, or structures, e.g., valve annulus andheart wall.

It is still further contemplated that the points at which an ECMprosthetic tissue valve is attached to a cardiovascular structure (orstructures) in a subject will serve as points of constraint that directthe remodeling of the ECM into cardiovascular tissue and valvestructures that are identical or substantially identical to properlyfunctioning native cardiovascular tissue and valve structures.

It is still further contemplated that, during circulation of epithelialand endothelial progenitor cells after placement of an ECM prosthetictissue valve on a cardiovascular structure (or structures), the surfacesof an ECM prosthetic tissue valve will rapidly become lined or coveredwith epithelial and/or endothelial progenitor cells.

As indicated above, in some embodiments of the invention, the proximalends of prosthetic tissue valves of the invention comprise an annularring that is designed and configured to securely engage the prosthetictissue valves to a valve annulus (and, hence, cardiovascular tissueassociated therewith).

As also indicated above, in some embodiments, the distal end ofprosthetic tissue valves comprising a conical shaped structural memberfurther comprise a structural ring.

According to the invention, the annular ring and structural ring canalso comprise various biocompatible materials and compositions formedtherefrom. Suitable biocompatible ring materials are disclosed inCo-Pending U.S. application Ser. No. 14/953,548, which is incorporatedby reference herein.

In some embodiments of the invention, the annular ring and/or structuralring comprise a polymeric composition comprising a biodegradablepolymeric material. According to the invention, suitable biodegradablepolymeric materials comprise, without limitation, polycaprolactone(PCL), Artelon® (porous polyurethaneurea), polyglycolide (PGA),polylactide (PLA), poly(ε-caprolactone) (PCL), poly dioxanone (apolyether-ester), poly lactide-co-glycolide, polyamide esters,polyalkalene esters, polyvinyl esters, polyvinyl alcohol, andpolyanhydrides.

According to the invention, the polymeric composition can furthercomprise a natural polymer, including, without limitation,polysaccharides (e.g. starch and cellulose), proteins (e.g., gelatin,casein, silk, wool, etc.), and polyesters (e.g., polyhydroxyalkanoates).

The polymeric composition can also comprise a hydrogel composition,including, without limitation, polyurethane, poly(ethylene glycol),poly(propylene glycol), poly(vinylpyrrolidone), xanthan, methylcellulose, carboxymethyl cellulose, alginate, hyaluronan, poly(acrylicacid), polyvinyl alcohol, acrylic acid, hydroxypropyl methyl cellulose,methacrylic acid, αβ-glycerophosphate, κ-carrageenan,2-acrylamido-2-methylpropanesulfonic acid, and β-hairpin peptide.

According to the invention, the polymeric composition can furthercomprise a non-biodegradable polymer, including, without limitation,polytetrafluoro ethylene (Teflon®) and polyethylene terephthalate(Dacron®).

In some embodiments of the invention, the polymeric compositioncomprises poly(urethane urea); preferably, Artelon® distributed byArtimplant AB in Goteborg, Sweden.

In some embodiments, the polymeric composition comprises poly(glycerolsebacate) (PGS).

In some embodiments of the invention, annular ring and/or structuralring and, hence, prosthetic valves formed therefrom comprise abiocompatible metal. According to the invention, suitable metalscomprise, without limitation, Nitinol®, stainless steel and magnesium.

In a preferred embodiment of the invention, the tubular shaped memberscomprise an ECM composition comprising acellular ECM derived from amammalian tissue source.

In a preferred embodiment, the conical shaped structural membersimilarly comprises an ECM composition comprising acellular ECM derivedfrom a mammalian tissue source.

In some embodiments, the annular ring and/or structural ring alsocomprise an ECM composition comprising acellular ECM derived from amammalian tissue source.

According to the invention, the ECM can be derived from variousmammalian tissue sources and methods for preparing same, such asdisclosed in U.S. Pat. Nos. 7,550,004, 7,244,444, 6,379,710, 6,358,284,6,206,931, 5,733,337 and 4,902,508 and U.S. application Ser. No.12/707,427; which are incorporated by reference herein in theirentirety.

The mammalian tissue sources include, without limitation, the smallintestine, large intestine, stomach, lung, liver, kidney, pancreas,peritoneum, placenta, heart, bladder, prostate, tissue surroundinggrowing enamel, tissue surrounding growing bone, and any fetal tissuefrom any mammalian organ.

The mammalian tissue can thus comprise, without limitation, smallintestine submucosa (SIS), urinary bladder submucosa (UBS), stomachsubmucosa (SS), central nervous system tissue, epithelium of mesodermalorigin, i.e. mesothelial tissue, dermal extracellular matrix,subcutaneous extracellular matrix, gastrointestinal extracellularmatrix, i.e. large and small intestines, tissue surrounding growingbone, placental extracellular matrix, omentum extracellular matrix,cardiac extracellular matrix, e.g., pericardium and/or myocardium,kidney extracellular matrix, pancreas extracellular matrix, lungextracellular matrix, and combinations thereof. The ECM can alsocomprise collagen from mammalian sources.

In some embodiments of the invention, the mammalian tissue sourcecomprises mesothelial tissue.

In some embodiments, the mammalian tissue source comprises an adolescentmammalian tissue source, e.g. tissue derived from a porcine mammal lessthan 3 years of age.

According to the invention, the ECM can also be derived from the same ordifferent mammalian tissue sources, as disclosed in Co-Pendingapplication Ser. Nos. 13/033,053 and 13/033,102; which are incorporatedby reference herein.

In a preferred embodiment of the invention, the ECM comprises sterilizedand decellularized (or acellular) ECM.

According to the invention, the ECM can be sterilized and decellularizedby various conventional means.

In some embodiments of the invention, the ECM is sterilized anddecellularized via applicant's proprietary process disclosed inCo-Pending U.S. application Ser. No. 13/480,205; which is expresslyincorporated by reference herein in its entirety.

In some embodiments of the invention, the ECM comprises crosslinked ECM.According to the invention, the ECM can be crosslinked by variousconventional materials and methods.

As stated above, in some embodiments of the invention, the ECMcomposition (and, hence, tubular shaped member and/or conical shapedstructural member and/or annular ring and/or structural ring formedtherefrom) further comprises at least one additional biologically activeagent or composition, i.e. an agent that induces or modulates aphysiological or biological process, or cellular activity, e.g., inducesproliferation, and/or Growth and/or regeneration of tissue.

According to the invention, suitable biologically active agents includeany of the aforementioned biologically active agents, including, withoutlimitation, the aforementioned growth factors, cells and proteins.

In some embodiments of the invention, the ECM composition (and, hence,tubular shaped member and/or conical shaped structural member and/orannular ring and/or structural ring formed therefrom) further comprisesat least one pharmacological agent or composition (or drug), i.e. anagent or composition that is capable of producing a desired biologicaleffect in vivo, e.g., stimulation or suppression of apoptosis,stimulation or suppression of an immune response, etc.

According to the invention, suitable pharmacological agents andcompositions include any of the aforementioned agents, including,without limitation, antibiotics, anti-viral agents, analgesics,steroidal anti-inflammatories, non-steroidal anti-inflammatories,anti-neoplastics, anti-spasmodics, modulators of cell-extracellularmatrix interactions, proteins, hormones, enzymes and enzyme inhibitors,anticoagulants and/or antithrombotic agents, DNA, RNA, modified DNA andRNA, NSAIDs, inhibitors of DNA, RNA or protein synthesis, polypeptides,oligonucleotides, polynucleotides, nucleoproteins, compounds modulatingcell migration, compounds modulating proliferation and growth of tissue,and vasodilating agents.

In some embodiments of the invention, the pharmacological agentcomprises an anti-inflammatory agent.

In some embodiments, the pharmacological agent comprises a statin, i.e.a HMG-CoA reductase inhibitor. According to an aspect of the invention,suitable statins include, without limitation, atorvastatin (Lipitor®),cerivastatin, fluvastatin (Lescol®), lovastatin (Mevacor®, Altocor®,Altoprev®), mevastatin, pitavastatin (Livalo ®, Pitava®), pravastatin(Pravachol®, Selektine®, Lipostat®), rosuvastatin (Crestor®), andsimvastatin (Zocor®, Lipex®). Several actives comprising a combinationof a statin and another agent, such as ezetimbe/simvastatin (Vytorin®),are also suitable.

It has been found that the noted statins exhibit numerous beneficialproperties that provide several beneficial biochemical actions oractivities in vivo; particularly, when the statins are a component of anECM composition comprising acellular ECM, i.e. a statin augmented ECMcomposition. The properties and beneficial actions are set forth inApplicant's U.S. Pat. No. 9,072,816 and Co-Pending application Ser. No.13/782,024, filed on Mar. 1, 2013 and Ser. No. 14/554,730, filed on Nov.26, 2014; which are incorporated by reference herein in their entirety.

In some embodiments of the invention, the pharmacological agentcomprises chitosan. As also set forth in detail in U.S. Pat. No.9,072,816, chitosan similarly exhibits numerous beneficial propertiesthat provide several beneficial biochemical actions or activities invivo; particularly when chitosan is a component of an ECM compositioncomprising acellular ECM.

As indicated above, it is contemplated that, following placement of anECM prosthetic tissue valve, i.e. a prosthetic tissue valve comprisingan ECM composition, on a cardiovascular structure (or structures) in asubject, e.g. valve annulus, and, hence, cardiovascular tissueassociated therewith, the ECM prosthetic tissue valve will induce“modulated healing” of the cardiovascular structure(s) andcardiovascular tissue associated therewith.

The term “modulated healing”, as used herein, and variants of thislanguage generally refer to the modulation (e.g., alteration, delay,retardation, reduction, etc.) of a process involving different cascadesor sequences of naturally occurring tissue repair in response tolocalized tissue damage or injury, substantially reducing theirinflammatory effect. Modulated healing, as used herein, includes manydifferent biologic processes, including epithelial growth, fibrindeposition, platelet activation and attachment, inhibition,proliferation and/or differentiation, connective fibrous tissueproduction and function, angiogenesis, and several stages of acuteand/or chronic inflammation, and their interplay with each other.

For example, in some embodiments of the invention, the ECM prosthetictissue valves of the invention are specifically formulated (or designed)to alter, delay, retard, reduce, and/or detain one or more of the phasesassociated with healing of damaged tissue, including, but not limitedto, the inflammatory phase (e.g., platelet or fibrin deposition), andthe proliferative phase when in contact with biological tissue.

In some embodiments, “modulated healing” means and includes the abilityof an ECM prosthetic tissue valve of the invention to restrict theexpression of inflammatory components. By way of example, according tothe invention, when a tubular member or conical shaped member (and/orannular ring and/or structural ring) of a prosthetic tissue valvecomprises a statin augmented ECM composition, i.e. a compositioncomprising ECM and a statin, and the ECM prosthetic tissue valve ispositioned proximate damaged biological tissue, e.g., attached to avalve annulus, the ECM prosthetic tissue valve restricts expression ofmonocyte chemoattractant protein-1 (MCP-1) and chemokine (C-C) motifligand 2 (CCR2).

In some embodiments of the invention, “modulated healing” means andincludes the ability of an ECM prosthetic tissue valve of the inventionto alter a substantial inflammatory phase (e.g., platelet or fibrindeposition) at the beginning of the tissue healing process. As usedherein, the phrase “alter a substantial inflammatory phase” refers tothe ability of a prosthetic tissue valve of the invention tosubstantially reduce the inflammatory response at a damaged tissue site,e.g. valve annulus, when in contact with tissue at the site.

In such an instance, a minor amount of inflammation may ensue inresponse to tissue injury, but this level of inflammation response,e.g., platelet and/or fibrin deposition, is substantially reduced whencompared to inflammation that takes place in the absence of an ECMprosthetic tissue valve of the invention.

The term “modulated healing” also refers to the ability of an ECMprosthetic tissue valve of the invention to induce host tissueproliferation, bioremodeling, including neovascularization, e.g.,vasculogenesis, angiogenesis, and intussusception, and regeneration oftissue structures with site-specific structural and functionalproperties, when disposed proximate damaged tissue, e.g. valve annulus.

Thus, in some embodiments of the invention, the term “modulated healing”means and includes the ability of an ECM prosthetic tissue valve of theinvention to modulate inflammation and induce host tissue proliferationand remodeling, when disposed proximate damaged tissue.

It is further contemplated that, during a cardiac cycle after placementof an ECM prosthetic tissue valve on a valve structure or structures,wherein the ECM prosthetic tissue valve is subjected to physicalstimuli, adaptive regeneration of the prosthetic tissue valve is alsoinduced.

By the term “adaptive regeneration,” it is meant to mean the process ofinducing modulated healing of damaged tissue concomitantly withstress-induced hypertrophy of an ECM prosthetic tissue valve of theinvention, wherein the ECM prosthetic tissue valve adaptively remodelsand forms functioning valve structures that are substantially identicalto native valve structures.

As indicated above, it is further contemplated that the points at whichan ECM prosthetic tissue valve is attached to a cardiovascular structure(or structures) in a subject will serve as points of constraint thatdirect the remodeling of the ECM into cardiovascular tissue and valvestructures that are substantially identical to properly functioningnative cardiovascular tissue and valve structures.

Referring now to FIGS. 2-5, two (2) embodiments of a prosthetic tissuevalve of the invention will be described in detail.

Referring first to FIGS. 2 and 3, in one embodiment of the invention,the prosthetic tissue valve 10 a comprises a continuous tubular member12 having first or “proximal” and second or “distal” ends 14, 16. Insome embodiments of the invention, the valve 10 a further comprises atleast one internal leaflet, such as disclosed in U.S. Pat. No. 8,709,076and Co-Pending U.S. application Ser. No. 13/804,683, which areincorporated by reference herein.

In some embodiments, the tubular member 12 comprises a leaflet forminginterior surface, such as disclosed in Co-Pending U.S. application Ser.Nos. 13/480,324 and 13/480,347, which are similarly incorporated byreference herein.

According to the invention, the tubular member 12 can comprise variousbiocompatible materials, including, without limitation, mammaliantissue, e.g., bovine tissue.

In some embodiments of the invention, the tubular member 12 comprises abiocompatible polymeric material. According to the invention, suitablepolymeric materials comprise Dacron®, polyether ether ketone (PEEK), andlike materials.

As indicated above, in some embodiments, the tubular member 12 comprisesan ECM composition comprising ECM from a mammalian tissue source.According to the invention, the ECM can be derived from variousmammalian tissue sources including, without limitation, small intestinesubmucosa (SIS), urinary bladder submucosa (UBS), stomach submucosa(SS), central nervous system tissue, mesodermal origin, i.e. mesothelialtissue, dermal extracellular matrix, subcutaneous extracellular matrix,gastrointestinal extracellular matrix, i.e. large and small intestines,tissue surrounding growing bone, placental extracellular matrix, omentumextracellular matrix, cardiac extracellular matrix, e.g., pericardiumand/or myocardium, kidney extracellular matrix, pancreas extracellularmatrix, lung extracellular matrix, and combinations thereof.

According to the invention, the ECM can also comprise collagen frommammalian sources.

As also indicated above, the ECM preferably comprises acellular ECM.

In some embodiments of the invention, the ECM composition and, hence,tubular member 12 formed therefrom, further comprises at least oneadditional biologically active agent or composition, i.e. an agent thatinduces or modulates a physiological or biological process, or cellularactivity, e.g., induces proliferation, and/or growth and/or regenerationof tissue.

According to the invention, suitable biologically active agents includeany of the aforementioned biologically active agents.

In some embodiments of the invention, the ECM composition and, hence,tubular member 12 formed therefrom, further comprises at least onepharmacological agent or composition (or drug), i.e. an agent orcomposition that is capable of producing a desired biological effect invivo, e.g., stimulation or suppression of apoptosis, stimulation orsuppression of an immune response, etc.

According to the invention, suitable pharmacological agents andcompositions include any of the aforementioned agents, including,without limitation, antibiotics and anti-inflammatories.

In a preferred embodiment of the invention, the distal end 16 of thetubular member 12 includes cardiovascular structure engagement means 18that is designed and configured to securely engage the member 12 and,hence, prosthetic tissue valve 10 a formed therefrom, to cardiovascularstructures, such as selective papillary muscles and/or cardiovasculartissue.

As illustrated in FIGS. 2 and 3, in some embodiments of the invention,the cardiovascular structure engagement means 18 comprises a pair ofvalve leaflet extensions 22 a, 22 b, which, in some embodiments of theinvention, extend from a valve leaflet to mimic the chordae tendineae.According to the invention, the valve leaflet extensions 22 a, 22 b canbe disposed at various positions about the periphery of the distal end16 of the tubular member 12.

In some embodiments of the invention, wherein the prosthetic tissuevalve 10 a is employed to replace a mitral valve, the leaflet extensions22 a, 22 b are preferably spaced at approximately 0° and 120° about theperiphery of the distal end 16 of the tubular member 12.

According to the invention, the valve leaflet extensions 22 a, 22 b canalso have various predetermined lengths to accommodate attachment todesired cardiovascular structures, e.g., selective papillary muscles.

The valve leaflet extensions 22 a, 22 b can also comprise the samematerial as the tubular member 12 or a different material, e.g. tubularmember 12 comprises SIS and the valve leaflet extensions 22 a, 22 bcomprise a polymeric material.

Referring now to FIGS. 4 and, 5, in a further embodiment of theinvention, the prosthetic tissue valve 10 a shown in FIGS. 2 and 3further comprises an annular ring 15 that is disposed on the proximalend 14 of the valve 10 a, forming valve 10 b. As indicated above,suitable annular rings and ring materials are disclosed in Co-PendingU.S. application Ser. No. 14/953,548.

Referring now to FIG. 6, placement of prosthetic tissue valve 10 aproximate a mitral valve region will be described in detail.

According to the invention, the valve 10 a is disposed proximate themitral valve region. The initial placement of the valve 10 a can beachieved by various conventional means, including limited access heartsurgery and percutaneous delivery.

The proximal end 14 of the valve 12 is then sutured to the valve annulus105. The valve leaflet extensions 22 a, 22 b are then attached directlyto the papillary muscles 119 a, 119 b.

It is contemplated that, following attachment of the valve leafletextensions 22 a, 22 b to the papillary muscles 119 a, 119 b, the valveleaflet extensions 22 a, 22 b fuse to the papillary muscles 119 a, 119 band, in some embodiments, the valve leaflet extensions 22 a, 22 bremodel and regenerate functioning native chordae tendineae.

As indicated above, when the prosthetic tissue valve 10 a (and valve 10b) comprises an ECM prosthetic tissue valve, it is also contemplatedthat the points at which the valve leaflet extensions 22 a, 22 b connectto the papillary muscles 119 a, 119 b and the proximal end 14 of thevalve 12 is attached to the valve annulus 105 will serve as points ofconstraint that direct the remodeling of the prosthetic tissue valve 10a (and valve 10 b) into valve tissue and/or valve structures, includingchordae tendineae, that are identical or substantially identical toproperly functioning native valve tissue and valve structures.

According to the invention, the valve leaflet extensions 22 a, 22 b andnoted placement and attachment thereof significantly enhances thestrength and, hence, structural integrity of the prosthetic tissuevalves 10 a, 10 b shown in FIGS. 2-5. The valve leaflet extensions 22 a,22 b and noted placement and attachment thereof also preserves thestructural integrity of the papillary muscles 119 a, 119 b.

The valve leaflet extensions 22 a, 22 b (and noted placement andattachment thereof) thus significantly reduces the risk of suturefailure and rupture of the prosthetic valve tissue proximate thepapillary muscles 119 a, 119 b. The valve leaflet extensions 22 a, 22 b(and noted placement and attachment thereof) also significantly reducethe risk of rupture of the papillary muscles 119 a, 119 b.

Referring now to FIGS. 7A and 7B, there is shown another embodiment of aprosthetic tissue valve of the invention (denoted “10 c”). Asillustrated in FIG. 7A, the prosthetic tissue valve 10 c comprises acontinuous conical shaped member 30.

In a preferred embodiment, the conical shaped member 30 similarlycomprises an ECM composition comprising acellular ECM derived from oneof the aforementioned mammalian tissue sources, including, withoutlimitation, small intestine submucosa (SIS), urinary bladder submucosa(UBS), mesothelial tissue, placental tissue and cardiac tissue.

As illustrated in FIG. 7A, the prosthetic tissue valve 10 c furthercomprises proximal and distal ends 32, 34. According to the invention,the proximal end 32 of the valve 10 c is sized and configured to engagea valve annulus region of a mammalian heart.

In some embodiments of the invention, the proximal end 32 of the valve10 c (and valves 10 d and 10 e, discussed below) has an outer diameterin the range of approximately 1.0 mm to 5 cm.

According to the invention, the conical shaped member 30 and, hence,prosthetic tissue valve 10 c can (and valves 10 d-10 e) comprise anylength. In some embodiments of the invention, prosthetic tissue valve 10c (and valves 10 d-10 e) has a length in the range of approximately 5 mmto 150 mm.

In some embodiments of the invention, the conical shaped member 30 and,hence, prosthetic tissue valve 10 c (and valves 10 d-10 e) has aproximal end diameter and length ratio in the range of 5:1 to 2:1.

As illustrated in FIGS. 7A and 7B, the prosthetic tissue valve 10 cfurther comprises a plurality of open regions 36 a-36 d that arepreferably disposed linearly (i.e. parallel to the longitudinal axis ofthe valve 10 c) over a portion of the length of the member 30. Accordingto the invention, the length and width of the open regions 36 a-36 d cancomprise any length or width.

In some embodiments of the invention, the open regions 36 a-36 d have alength that is in the range of approximately 10% to 98% of the overalllength of the conical shaped member 30.

In some embodiments, the width of the open regions 36 a-36 d is in therange of approximately 1 mm to 30 mm.

According to the invention, the open regions 36 a-36 d can have the samelength and width or different lengths and widths. In some embodiments ofthe invention, the open regions 36 a-36 d have the same length andwidth.

Referring now to FIG. 7C, there is shown another embodiment of theprosthetic tissue valve 10 c that is shown in FIG. 7A. As illustrated inFIG. 7C, the prosthetic tissue valve, now denoted 10 d, furthercomprises an annular ring 38 that is designed and configured to securelyengage the prosthetic tissue valve 10 d to a valve annulus (and, hence,cardiovascular tissue associated therewith).

According to the invention, the outer circumference of the annular ring38 can comprise various dimensions. In some embodiments of theinvention, the ratio of the circumference of the annular ring 38 to theoperative valve circumference of prosthetic tissue valve 10 c (andprosthetic tissue valves 10 d-10 h) is in the range of approximately 1:1to approximately 3:1.

Referring now to FIG. 7D, there is shown yet another embodiment of theprosthetic tissue valve 10 c that is shown in FIG. 7A. As illustrated inFIG. 7D, the prosthetic tissue valve, now denoted 10 e, furthercomprises a structural ring 40 that is disposed on the distal end 34 ofthe valve 10 e.

As indicated above, according to the invention, the annular ring 38and/or structural ring 40 can comprise various biocompatible materials,such as disclosed in Co-Pending U.S. application Ser. No. 14/953,548.

In some embodiments of the invention, the annular ring 38 and/orstructural ring 40 comprise a polymeric composition comprising one ofthe aforementioned biodegradable polymeric materials.

In some embodiments, the annular ring 38 and/or structural ring 40comprise poly(urethane urea).

In some embodiments, the annular ring 38 and/or structural ring 40comprise poly(glycerol sebacate) (PGS).

In some embodiments, the annular ring 38 and/or structural ring 40comprise an ECM composition comprising acellular ECM derived from one ofthe aforementioned mammalian tissue sources.

Referring now to FIGS. 8A and 8B there is shown another embodiment of aprosthetic tissue valve of the invention, where FIG. 8A illustrates theprosthetic tissue valve, denoted 10 f, in a pre-formed configuration andFIG. 8B illustrates the prosthetic tissue valve 10 f in a formedconfiguration.

As illustrated in FIGS. 8A and 8B, in a preferred embodiment of theinvention, the prosthetic tissue valve 10 f comprises a base member 50having a plurality of ribbons 56 that extend from the proximal end 52 tothe distal end 54 of the base member 50.

In a preferred embodiment, the base member 50 similarly comprises an ECMcomposition comprising acellular ECM derived from one of theaforementioned mammalian tissue sources.

As illustrated in FIG. 8B, in some embodiments, the ribbons 56 of theformed valve 10 f taper to a substantially coincident point 55, whereinthe base member 50 has a substantially conical shape.

According to the invention, the base member 50 can comprise any numberof ribbons 56. In some embodiments of the invention, the base member 50has four (4) equally spaced ribbons 56.

According to the invention, the proximal end 52 of the valve 10 f issimilarly sized and configured to engage an annular region of amammalian heart.

According to the invention, the proximal end 52 of the valve 10 f (andprosthetic tissue valves 10 g and 10 h, discussed below) can similarlycomprise a circumference, i.e. operative valve circumference, in therange of approximately 20 mm to 220 mm.

According to the invention, the prosthetic tissue valve 10 f (andprosthetic tissue valves 10 g and 10 h, discussed below) can alsocomprise any length. In some embodiments of the invention, theprosthetic tissue valve 10 f (and prosthetic tissue valves 10 g and 10h) has a length in the range of approximately 5 mm to 150 mm. In someembodiments of the invention, the prosthetic tissue valve 10 f (andprosthetic tissue valves 10 g and 10 h) has a length in the range ofapproximately 10 mm to 100 mm.

In some embodiments of the invention, prosthetic tissue valve 10 f (andvalves 10 g and 10 h) has a proximal end diameter and length ratio inthe range of 5:1 to 2:1.

Referring now to FIG. 8C, there is shown another embodiment of theprosthetic tissue valve 10 f that is shown in FIG. 8B. As illustrated inFIG. 8C, the prosthetic tissue valve, now denoted 10 g, similarlycomprises annular ring 38, which is designed and configured to securelyengage the prosthetic tissue valve 10 g to a valve annulus (and, hence,cardiovascular tissue associated therewith).

Referring now to FIG. 8D, there is shown yet another aspect of theprosthetic tissue valve 10 f that is shown in FIG. 8B. As illustrated inFIG. 8D, the prosthetic tissue valve, now denoted 10 h, furthercomprises a structural ring 40 that is disposed on the distal end 34 ofthe valve 10 h.

According to the invention, the structural ring 40 is preferably sizedand configured to receive ribbons 56 therein in close proximity to eachother, as shown in FIG. 8D.

According to the invention, the proximal end of the prosthetic tissuevalves of the invention can be secured to a valve annulus by variousconventional means, such as suturing the proximal end (with or withoutan annular ring 38) directly to the valve annulus tissue.

In some embodiments of the invention, ribbons 56 of prosthetic valves 10f, 10 g and 10 h are connected via a constraining band that ispositioned between the proximal and distal ends 52, 54 of the valves 10f, 10 g, 10 h. According to the invention, the restraining band cancomprise the same material as the valve base member 50 or a differentmaterial.

In some embodiments of the invention, ribbons 56 of prosthetic valves 10f, 10 g and 10 h are restrained at a predetermined valve region, e.g.,mid-point, between the proximal and distal ends 52, 54 of the valves 10f, 10 g, 10 h via a supplemental structural ring.

As indicated above, in a preferred embodiment of the invention, theconical shaped member 30 of prosthetic tissue valves 10 c-10 d and basemember 50 (and, hence, ribbons 56) of prosthetic tissue valves 10 f-10 hcomprise an ECM composition comprising acellular ECM derived from one ofthe aforementioned mammalian tissue sources.

In some embodiments of the invention, the mammalian tissue sourcecomprises small intestine submucosa (SIS).

In some embodiments, the mammalian tissue source comprises mesothelialtissue.

In some embodiments of the invention, the ECM composition and, hence,conical shaped member 30 of prosthetic tissue valves 10 c-10 d and basemember 50 (and, hence, ribbons 56) of prosthetic tissue valves 10 f-10h, further comprises at least one additional biologically active agentor composition, i.e. an agent that induces or modulates a physiologicalor biological process, or cellular activity.

In some embodiment, the annular ring 38 and/or structural ring 40comprise at least one additional biologically active agent orcomposition.

According to the invention, suitable biologically active agents includeany of the aforementioned biologically active agents.

In some embodiments of the invention, the ECM composition and, hence,conical shaped member 30 of prosthetic tissue valves 10 c-10 d and basemember 50 (and, hence, ribbons 56) of prosthetic tissue valves 10 f-10h, further comprises at least one pharmacological agent or composition(or drug), i.e. an agent or composition that is capable of producing adesired biological effect in vivo.

In some embodiment, the annular ring 38 and/or structural ring 40comprise at least one additional pharmacological agent or composition.

According to the invention, suitable pharmacological agents andcompositions include any of the aforementioned agents, including,without limitation, antibiotics, and anti-inflammatories.

In some embodiments of the invention, the conical shaped member 30 ofprosthetic tissue valves 10 c-10 d and base member 50 (and, hence,ribbons 56) of prosthetic tissue valves 10 f-10 h comprise an outercoating.

In some embodiments, the annular ring 38 and/or structural ring 40comprise an outer coating.

In some embodiments of the invention, the coating comprises an ECMcomposition comprising acellular ECM form one of the aforementionedmammalian tissue sources.

In some embodiments, the ECM composition further comprises at least oneof the aforementioned biologically active agents or compositions.

In some embodiments, the ECM composition further comprises at least oneof the aforementioned pharmacological agents or compositions.

In some embodiments of the invention, the coating comprises one of theaforementioned polymeric compositions.

Referring now to FIG. 9, placement of prosthetic tissue valve 10 d in amitral valve region will now be described in detail.

According to the invention, prior to placement of prosthetic tissue vale10 d (as well as valves 10 c and 10 e-10 h) in a mitral valve region,the mitral valve 102 and chordae tendinae 103 a, 103 b can be removed orretained. Thus, in some embodiments of the invention, the mitral valve102 and chordae tendinae 103 a, 103 b are retained. In some embodiments,the mitral valve 102 and chordae tendinae 103 a, 103 b are removed.

After the mitral valve annulus region 107 is prepared, and, if elected,the mitral valve 102 and chordae tendinae 103 a, 103 b are removed, theprosthetic tissue valve 10 d is disposed proximate the mitral valveannulus region 107.

According to the invention, the initial placement of the prosthetictissue valve 10 d (as well as tissue valves 10 a-10 c and 10 e-10 h,discussed below) can be achieved by various conventional means,including limited access heart surgery and percutaneous transatrial,i.e. through the left atrium, and transapical delivery.

After disposing the prosthetic tissue valve 10 d proximate the mitralvalve region 107, the proximal end 32 of the prosthetic tissue valve 10d is secured to the valve annulus 105.

Referring now to FIG. 10, placement of prosthetic tissue valve 10 h in amitral valve region will now be described in detail.

After the mitral valve annulus region 107 is prepared and, if elected,the mitral valve 102 and chordae tendinae 103 a, 103 b are removed, thevalve 10 h is similarly disposed proximate the mitral valve annulusregion 107. The proximal end 32 of the prosthetic tissue valve 10 h isthen secured to the valve annulus 105.

Placement of prosthetic tissue valves 10 f and 10 g in a mitral valveregion are similar to placement of prosthetic tissue valve 10 h.However, in some embodiments of the invention, the distal ends 54 of theribbons 56 proximate the coincident point 55 of prosthetic tissue valves10 f and 10 g are connected to the inner surface of the ventricle 106via at least one active fixation lead (not shown).

As illustrated in FIG. 11, in some embodiments of the invention, theribbons 56 are threaded through the heart wall 101 and attached on theoutside of the heart 100. In some embodiments, the ribbons 56 aresecured into the heart wall muscle via cork-screw mechanism 59.

In some embodiments of the invention, the prosthetic tissue valves 10c-10 h described above further comprise a supplemental supportstructure. In some embodiments, the support structure comprises at leastone internal biocompatible support ring that is disposed between theproximal and distal end of the valve. In some embodiments, the supportstructure comprises a biocompatible multi-link stent structure.

In some embodiments of the invention, the prosthetic tissue valves 10c-10 h described above further comprise at least one internal pre-formedleaflet, such as disclosed in Applicant's U.S. Pat. Nos. 8,709,076,9,011,526, 8,257,434 and 7,998,196, which are incorporated by referenceherein.

As indicated above, it is contemplated that, when the prosthetic tissuevalves 10 c-10 h comprise an ECM composition comprising acellular ECM(i.e. ECM prosthetic tissue valves), upon placement of the ECMprosthetic tissue valves 10 c-10 h to a valve structure, e.g., valveannulus 105, modulated healing of the valve structure and connectingcardiovascular structure tissue will be effectuated.

It is further contemplated that, following placement of the ECMprosthetic tissue valves 10 c-10 h in a subject on a cardiovascularstructure (or structures) in a subject, the ECM prosthetic tissue valves10 c-10 h will become populated with cells from the subject that willgradually remodel the ECM into cardiovascular tissue and tissue (and,hence, valve) structures.

It is further contemplated that, following placement of the ECMprosthetic tissue valves 10 c-10 h in a subject on a cardiovascularstructure (or structures) in a subject, stem cells will migrate to theECM prosthetic tissue valves 10 c-10 h from the point(s) at which thevalves are attached to the cardiovascular structure, e.g., valveannulus, or structures, e.g., valve annulus and heart wall.

It is still further contemplated that the points at which the ECMprosthetic tissue valves 10 c-10 h are attached to a cardiovascularstructure (or structures) in a subject will serve as points ofconstraint that direct the remodeling of the ECM into cardiovasculartissue and valve structures that are identical or substantiallyidentical to properly functioning native cardiovascular tissue and valvestructures.

It is still further contemplated that, during circulation of epithelialand endothelial progenitor cells after placement of the ECM prosthetictissue valves 10 c-10 h on a cardiovascular structure (or structures),the surfaces of an ECM prosthetic tissue valves 10 c-10 h will rapidlybecome lined or covered with epithelial and/or endothelial progenitorcells.

As will readily be appreciated by one having ordinary skill in the art,the present invention provides numerous advantages compared to prior artprosthetic valves. Among the advantages are the following:

-   -   The provision of improved methods for securely attaching        prosthetic valves to cardiovascular structures and/or tissue;    -   The provision of prosthetic tissue valves having means for        secure, reliable, and consistently highly effective attachment        to cardiovascular structures and/or tissue;    -   The provision of improved prosthetic tissue valves and methods        for attaching same to cardiovascular structures and/or tissue        that maintain or enhance the structural integrity of the valve        when subjected to cardiac cycle induced stress;    -   The provision of improved prosthetic tissue valves and methods        for attaching same to cardiovascular structures and/or tissue        that preserve the structural integrity of the cardiovascular        structure(s) when attached thereto;    -   The provision of prosthetic tissue valves that induce modulated        healing, including host tissue proliferation, bioremodeling and        regeneration of new tissue and tissue structures with        site-specific structural and functional properties;    -   The provision of prosthetic tissue valves that induce adaptive        regeneration;    -   The provision of prosthetic tissue valves that are capable of        administering a pharmacological agent to host tissue and,        thereby produce a desired biological and/or therapeutic effect;    -   The provision prosthetic tissue valves that can be implanted        without removal of the native AV valve;    -   The provision prosthetic tissue valves that can be implanted        without a cardiopulmonary bypass apparatus;    -   The provision prosthetic tissue valves that can be positioned        proximate a valve annulus transvascularly; and    -   The provision prosthetic tissue valves that can be positioned        proximate a valve annulus transapically.

Without departing from the spirit and scope of this invention, one ofordinary skill can make various changes and modifications to theinvention to adapt it to various usages and conditions. As such, thesechanges and modifications are properly, equitably, and intended to be,within the full range of equivalence of the following claims.

What is claimed is:
 1. A prosthetic valve, comprising: a conical shapedsheet member comprising a first extracellular matrix (ECM) composition,said first ECM composition comprising first acellular ECM from a firstmammalian tissue source, said sheet member further comprising alongitudinal axis, inner and outer surfaces, a proximal annulusengagement end, said sheet member further comprising a plurality of openslit regions that are disposed uniformly on linear planes that areparallel to said sheet member longitudinal axis, said sheet memberfurther comprising a proximal annulus engagement end diameter and lengthratio in the range of 5:1 to 2:1, said sheet member being configured toinduce host cell and tissue proliferation, remodeling of damagedcardiovascular tissue and regeneration of new cardiovascular tissue andtissue structures with site-specific structural and functionalproperties, when said sheet member is disposed proximate a valveannulus.
 2. The prosthetic valve of claim 1 wherein said sheet memberhas a length from said proximal annulus engagement end to said distalend in the range of 5 mm to 150 mm.
 3. The prosthetic valve of claim 2,wherein said slit regions comprise in the range of 10% to 98% of saidsheet member length.
 4. The prosthetic valve of claim 1, wherein saidfirst mammalian tissue source is selected from the group consisting ofsmall intestine submucosa (SIS), urinary bladder submucosa (UBS),urinary basement membrane (UBM), liver basement membrane (LBM), stomachsubmucosa (SS), mesothelial tissue, subcutaneous extracellular matrix,large intestine extracellular matrix, placental extracellular matrix,omentum extracellular matrix, heart extracellular matrix and lungextracellular matrix.
 5. The prosthetic valve of claim 1, wherein saidfirst ECM composition further comprises at least one exogenously addedfirst biologically active agent.
 6. The prosthetic valve of claim 5,wherein said first biologically active agent comprises a cell selectedfrom the group consisting of a human embryonic stem cell, fetalcardiomyocyte, myofibroblast, and mesenchymal stem cell.
 7. Theprosthetic valve of claim 5, wherein said first biologically activeagent comprises a first growth factor selected from the group consistingof a transforming growth factor-alpha (TGF-α), transforming growthfactor-beta (TGF-β), fibroblast growth factor-2 (FGF-2), and vascularepithelial growth factor (VEGF).
 8. The prosthetic valve of claim 1,wherein said first ECM composition further comprises at least a firstpharmacological agent.
 9. The prosthetic valve of claim 8, wherein saidfirst pharmacological agent comprises a first agent selected from thegroup consisting of an antibiotic, anti-viral agent, analgesic,anti-inflammatory, anti-neoplastic, anti-spasmodic, and anticoagulantand antithrombic agent.
 10. The prosthetic valve of claim 8, whereinsaid first pharmacological agent comprises a first statin selected fromthe group consisting of atorvastatin, cerivastatin, fluvastatin,lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin andsimvastatin.
 11. The prosthetic valve of claim 1, wherein said sheetmember further comprises an annulus ring, said annulus ring beingdisposed on said proximal annulus engagement end of said sheet member.12. The prosthetic valve of claim 11, wherein said annulus ringcomprises a second ECM composition, said second ECM compositioncomprising second acellular ECM from a second mammalian tissue sourceselected from the group consisting of small intestine submucosa (SIS),urinary bladder submucosa (UBS), urinary basement membrane (UBM), liverbasement membrane (LBM), stomach submucosa (SS), mesothelial tissue,subcutaneous extracellular matrix, large intestine extracellular matrix,placental extracellular matrix, ornomentum extracellular matrix, heartextracellular matrix and lung extracellular matrix.
 13. The prostheticvalve of claim 12, wherein said second ECM composition further comprisesat least one exogenously added second biologically active agent.
 14. Theprosthetic valve of claim 13, wherein said second biologically activeagent comprises a growth factor selected from the group consisting ofTGF-α, TGF-β, FGF-2, and VEGF.
 15. The prosthetic valve of claim 11,wherein said annulus ring comprises poly(urethane urea).
 16. Theprosthetic valve of claim 11, wherein said annulus ring comprisespoly(glycerol sebacate).
 17. The prosthetic valve of claim 1, whereinsaid sheet member further comprises a structural ring that is disposedon said distal end of said sheet member, said structural ring beingconfigured to receive said distal end of said sheet member therein. 18.The prosthetic valve of claim 17, wherein said structural ring comprisesa shape memory alloy.
 19. The prosthetic valve of claim 17, wherein saidstructural ring comprises poly(urethane urea).
 20. The prosthetic valveof claim 17, wherein said structural ring comprises poly(glycerolsebacate).
 21. The prosthetic valve of claim 1, wherein said sheetmember further comprises an outer coating comprising a pharmacologicalcomposition.